The present invention is directed to methods of treating a variety of diseases, disorders and conditions using agents that, effectively, serve as substance P antagonists. The agents are peptidases that selectively cleave at Xaa-Pro amino acid residues.
Substance P is a peptide 11 amino acids in length and is a member of the tachykinin family (see U.S. Pat. No. 4,680,283). It is a neurotransmitter that is released by nerve endings in both the central and peripheral nervous systems. Among the numerous biological sites innervated by substance P-releasing neurons are the skin, intestines, stomach, bladder and cardiovascular system (see U.S. Pat. No. 6,146,636).
Because of its wide distribution, a very large and varied group of disorders have been associated with excessive production of substance P. In particular, substance P has been reported to be involved in the transmission of pain (particularly pain associated with migraine headache), in arthritis, in gastrointestinal disorders, and in emisis (Otsuka, et al., Ciba Foundation Symp 91:13-34 (1982); Otsuka, et al., Tips 8:506-510 (1987); Sandberg, et al., J. Med. Chem. 25:1009 (1982); Levine, et al., Science 226:547-549 (1984); Mantyh, et al., Neurosci. 25:817-837 (1988); Tattersall, et al., Eur. J. Pharmacol. 250:R5-R6 (1993); Gronblad, et al., J. Rheumatol. 15:1807-1810 (1988)). Excessive levels of substance P are also believed to contribute to allergic conditions, vasospastic conditions, neurodegenerative disorders and immunological disorders (Hamelet, et al., Can. J. Pharmacol. Physiol. 66:1361-1367 (1988); Lotz, et al., Science 241:1218-1221 (1988); Kimball, et al., Immunol. 141:3464-3569 (1988); Mantyh, et al., Proc. Nat""l Acid Sci. U.S.A. 85:3235-3239 (1988); Yankner, et al., Science 250:279-282 (1990)).
There have also been reports suggesting that substance P may contribute to certain types of cancer, to autoimmune diseases and to disorders of bladder function (Langdon, et al., Cancer Res. 52:4554-4557 (1992); EP 436 334; Luber-Narod, et al, Lancet pg. 1239, May 16, 1992). Finally, there are suggestions in the literature that abnormal substance P levels are associated with arthritic diseases, dysthymic disorders, urinary disorders, collagen-related diseases, ophthalmic diseases, drug withdrawal syndromes and certain CNS disorders such as psychoses and schizophrenia (EP 394 989; EP 436,334; Maggi, et al. J. Auton. Pharmacol. 13:23-93 (1993)).
Given the extremely broad array of pathologies that substance P has been found to contribute in, it is not surprising that many different substance P antagonists have been developed and tested in the treatment of diseases and conditions. Among the numerous reports that have appeared in the literature discussing such antagonists are the following: U.S. Pat. Nos. 6,146,636; 4,472,305; 4,839,465; EP 499313; EP 522808; WO 93/01165; WO 93/09116; EP 514274; and WO 93/01169. Many of the approaches taken to antagonizing P activity have focused upon agents that bind to and block receptors for this peptide. However, other approaches may be taken to antagonizing substance P activity and these may contribute to the treatment of all of the diseases and conditions described above.
The present invention is based upon the concept that peptidases that cleave selectively at Xaa-Pro amino acid residues may be administered to patients as a treatment for diseases, disorders and conditions associated with abnormally elevated levels of substance P. The peptidases cleave the first, 2 to 4 residues of substance P thereby producing a peptide, substance P 5-11 that can no longer effectively bind to and activate receptor. Thus, the peptidases act essentially as xe2x80x9cantagonistsxe2x80x9d by reducing the available levels of intact peptide ligand. They may be administered either systemically or locally for the treatment of any of the disorders reported in the literature as being amenable to treatment with substance P antagonists.
In its broadest aspect, the present invention is directed to a method of treating a patient for a substance P-related disease, disorder or condition (collectively xe2x80x9cmaladyxe2x80x9d) in which a therapeutically effective amount of a peptidase that cleaves selectively at Xaa-Pro sequences is administered. The term xe2x80x9ctherapeutically effective amountxe2x80x9d is a dosage sufficient to produce a significant reduction in one or more symptoms associated with the disease or disorder being treated. For example, in the treatment of conditions such as migraine headache, neuropathic pain, arthritis and inflammatory conditions, a therapeutically effective amount would be a dosage sufficient to reduce the amount of pain or discomfort experienced by the patient. Similarly, a therapeutically effective amount would be a dosage sufficient to reduce the excessive motility associated with conditions such as irritable bowel syndrome or to reduce the rate of tumor growth in small cell carcinoma of the lung. The substance P-related maladies that may be treated are selected from the group consisting of CNS disorders; addiction withdrawal; neuropathic pain; postherpetic pain; neurodegenerative disorders; autoimmune diseases; disorders of the gastrointestinal tract; vasospastic diseases, skin disorders; collagen-related disorders; cardiovascular diseases and conditions; urinary tract disorders; arthritic diseases; ophthalmic diseases; cancer; oedema; emesis; dysthymic disorders; and reflex sympathetic dystrophy.
Preferred maladies amenable to the present treatment method include the following:
a) CNS disorders such as psychosis, anxiety and depression;
b) addiction withdrawal from alcohol or a narcotic;
c) neuropathic pain or postherpetic pain;
d) neurodegenerative maladies such as Alzheimer""s disease; AIDS-related dementia, Parkinson""s disease, amyotrophic lateral sclerosis, Huntington""s disease, and Down""s syndrome;
e) autoimmune diseases such as systemic lupus erythmatosus and multiple sclerosis;
f) disorders of the gastrointestinal tract such as colitis, Crohn""s disease and irritable bowel syndrome;
g) vasospastic diseases such as migraine headache, Reynaud""s disease and angina;
h) disorders or conditions of the skin such as sunburn, psoriasis, dermatitis, uticaria, and inflammation (e.g., due to exposure to poison ivy);
i) collagen-related disorders such as fibrositis, scleroderma, and eosinophilic fascioliasis;
j) hypertension or other cardiovascular diseases and conditions;
k) urinary tract disorders such as incontinence, cystitis, bladder hyper-reflexia, and bladder hypermotility;
l) arthritic diseases such as rheumatoid arthritis and osteoarthritis;
m) ophthalmic diseases or conditions such as proliferative vitreoretinopathy, ocular injury and conjunctivitis;
n) small cell carcinoma of the lung and other cancers; and
o) oedema, emesis, dysthymic disorders and reflex sympathetic dystrophy.
As discussed above, the present treatment method involves the administration of a peptidase that cleaves selectively at Xaa-Pro residues. Xaa represents any of the 20 amino acids commonly found in the proteins of animals. The term xe2x80x9cselectively cleavesxe2x80x9d indicates that the peptidase acts at essentially only these sites in peptides. Preferably, the method utilizes exopeptidases selected from dipeptidyl peptidase IV, quiescent cell proline dipeptidase, dipeptidyl peptidase 8 and attractin. In each case, it is the human form of the peptidase that is preferred. However, peptidases from other species, (e.g., those secreted by Aspergillus fumigatus) may also be used provided they have the required specificity. In all cases, it is expected that a therapeutically effective dose for any of the peptidases will be between 1 microgram and 1 milligram. Typically, between 5 micrograms and 500 micrograms will be used.